Solifenacin (1-azabicyclo[2.2.2]oct-8-yl(1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate) is known in the art as a urinary antispasmodic useful for treating overactive bladder with or without urge incontinence. Solifenacin was disclosed in EP 0 801 067 together with the oxalate salt thereof.
Solifenacin is presently being sold as solifenacin succinate (Vesicare®) by Astellas Pharma. Solifenacin succinate was first disclosed in EP 1 714 965 A1, wherein it is also disclosed that the succinate salt results in a purer end product. Other salts of solifenacin, such as the tartrate, maleate, and glutarate salts thereof are disclosed in WO 2008/011462, WO 2008/077357, WO 2009/087664, and WO 2010/012459.
Solifenacin succinate does, however, display certain stability problems. In US 2008/039516 and US 2008/0103171 it is disclosed how solifenacin succinate lacks stability when formulated by a wet granulation process. This is, according to US 2008/039516 and US 2008/0103171, due to formation of the amorphous form of solifenacin succinate during the manufacturing process. It was found that a content of the amorphous form of 77% or less was necessary to maintain product stability. Otherwise, the amount of the main degradation product, an oxidized form of solifenacin (labelled “F1” in the two US publications), will increase above the acceptable level of 0.4%.
It was additionally found that using polyethylene glycol (PEG) as a binder for the granulation avoided the stability problems, irrespective of the manufacturing process. Another proposed solution for maintaining the impurity below 0.4% was to adjust the moisture content in the solifenacin succinate during wet granulation.
According to the guidelines of The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) section Q3A(R2), Impurities in new drug substances, the qualification threshold for a known impurity must be 0.15% or less.
Moreover, the “Impurity F1” as an oxidized form of Solifenacin may be considered as a potential genotoxic impurity. In such case, the qualification threshold would be much lower than 0.15%.
Therefore, despite the attempts in the art for finding solutions for this stability problem, it is necessary to reduce the amount of “Impurity F1” even further.
For other salts of solifenacin, WO 2010/012459 discloses that grinding of the salts in crystalline form leads to the amorphous form. In other words, the salts disclosed in WO 2010/012459 become amorphous under the conditions used for preparing tablets containing the salts. These salts are therefore likely to experience the same stability problems as the succinate salt.
The state of the art reveals several ways to obtain Solifenacin. Most of them have as a common characteristic the use of 3R-quinuclidinol. Solifenacin was first synthesized in EP 0 801 067 by reacting 1-phenyl-1,2,3,4-tetrahydroisoquinoline with ethyl chloroformate. The resulting carbamate was subsequently reacted with quinuclidinol in the presence of sodium hydride, resulting in solifenacin final compound together with some diastereoisomeric and enantiomeric impurities. The carbamate and the quinuclidinol were reacted at a molar ratio of 1:1. No information is provided concerning the purity of the end product.
In WO 2008/011462 is disclosed a similar synthesis for preparing solifenacin, using the same reactants in toluene as a solvent. It is specified that the amount of 3R-quinuclidinol should be less than 1.5 molar equivalents due to the high cost of this reagent. WO 2009/139002 concerns the recovery of 3R-quinuclidinol from the mother liquors obtained from the preparation of solifenacin. Sodium hydroxide or potassium hydroxide is added to the mother liquor for recovering 3R-quinuclidinol. The molar ratio of 3R-quinuclidinol to carbamate is around 3:1. No information is provided concerning the yield of recovered 3R-quinuclidinol.
The final solifenacin product being prepared for formulation as a medicine must be of the required purity. Therefore, it has been proposed to use various salts of solifenacin for purifying the final product in EP 1 714 965 A1 (succinate salt used for purification), WO 2008/077357 (tartrate salt used for purification), and WO 2009/087664 (hydrochloride and oxalate salts used for purification).
There is, however, still a need for a solifenacin salt of higher stability than the commercially sold succinate salt, as well as pharmaceutical formulations thereof, in order to ensure the shelf-life of the commercial product during distribution and sale. In addition, there is also still a need for a more efficient process for preparing solifenacin and salts thereof with higher yields and a higher purity of the final product. There is a further need for an improved recovery of 3R-quinuclidinol.